Dabigatran etexilate and process for its preparation was first disclosed in WO 98/37075. The disclosed process involves the reaction of 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride (herein after referred as dabigatran hydrochloride) with hexylchloroformate in presence of potassium carbonate in tetrahydrofuran/water provides 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino) phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonylethyl)amide (herein after referred as dabigatran etexilate) and further conversion to its mesylate salt is not disclosed. The purity & yield of dabigatran etexilate prepared as per the disclosed process is not satisfactory, and also the said process involves chromatographic purification. As the chromatographic purification is expensive and difficult to implement on the large scale. Hence the said process is not suitable for commercial scale up.
Moreover, the said process involves the usage of dabigatran hydrochloride, which degrades to form impurities and results in the formation of dabigatran etexilate with low purity. In view of intrinsic fragility of dabigatran hydrochloride, there is a need in the art to develop a stable salt form of 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl)amide, which enhances the purity of the final compound.
The process for the preparation of mesylate salt of dabigatran etexilate and its polymorphic forms was disclosed in US 2005/234104. The disclosed process involves the reaction of dabigatran etexilate with methane sulphonic acid in acetone to provide dabigatran etexilate mesylate. The purity of the obtained crystalline dabigatran etexilate mesylate was not satisfactory i.e., around 97-98% by HPLC. There is no specific purification process disclosed for the purification of dabigatran etexilate mesylate.
Hence there is a need in the art to develop an improved process for the preparation of dabigatran etexilate mesylate with a high purity and yield. And also there is a necessity to provide a purification method for dabigatran etexilate mesylate as well as the isolation, characterization and synthesis of impurities formed in the preparation of dabigatran etexilate and its salts.
Dabigatran etexilate mesylate as prepared by the prior art processes may contain 2-(N-(3-ethoxy-3-oxopropyl)-2-((4-(N′-(hexyloxycarbonyl)carbamimidoyl)phenyl amino)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)pyridine-1-oxide (herein designated as “N-oxide impurity”); 3-(2-((4-(N′-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido) propanoic acid (herein designated as “Acid impurity”) as impurities and represented by the following structural formula:

Other than the above impurities, two more impurities are observed in HPLC at 0.845 RRT and 1.278 RRT respectively. The impurity at 0.845 RRT is herein designated as impurity-X and impurity at 1.278 RRT is herein designated as Impurity-Y. In the present invention N-oxide and acid impurities were isolated and characterized.